Bone Abstracts

Antiresorptives consistently improve bone mass and structural strength in normally- and under-loaded bones, but concerns have been raised regarding potential effects on skeletal adaptation to fatigue loading, including damage accumulation and atypical fractures. We thus inhibited or activated osteoclasts with OPG-Fc or RANKL treatment, respectively, and evaluated bone damage and strength after fatigue in the early and later phases of repair. Adult male mice were treated with RANKL (2 mg/kg/day), OPG-Fc (5 mg/kg 2/wk) or PBS (Veh). Axial compression (14 N, 3 Hz, 20 min) was applied to the tibia two days after initiating OPG-Fc or RANKL, with treatment continuing until sacrifice 1 or 28 days later (n=6 per group). We assessed cortical damage, bone mass, microarchitecture, and axial compressive strength. RANKL and OPG induced the expected changes, with bone resorption (serum TRAP5b) rapidly increasing and decreasing respectively, resulting in lower and higher bone mass/structure/strength in non-fatigued tibiae after 28 days. Fatigue rapidly increased cracks and resulted in a reactive callus that was present at day 28. OPG and RANKL did not affect crack accumulation one day after fatigue nor periosteal BFR 28 days after fatigue. However after 28 days, OPG decreased crack density and increased bone mass and strength, while RANKL had the opposite effect. Regression analysis across all groups indicate that total aBMD, proximal TbBV/TV and midshaft CtBV were positively associated with peak load (r²=0.67-0.76, all P<0.0001). In summary, OPG-Fc decreased cracks, likely due to increased bone volume and improved strength. Therefore, in this murine model of stress-induced damage, RANKL inhibition did not cause bone fragility or damage accumulation.